title: Identification of a novel complex BRAF mutation associated with major clinical response to vemurafenib in a patient with metastatic melanoma.
abstract: OBJECTIVE
  There is an increasing interest in BRAF V600 mutations in melanomas and their associated sensitivity to vemurafenib, a BRAF inhibitor. However, physicians cannot find information in the literature about vemurafenib response for rare and/or atypical BRAF mutations.
  
  
  METHODS
  We describe the identification of a novel complex BRAF mutation associated with major clinical response to vemurafenib in a patient with metastatic melanoma. Using a pyrosequencing method, we determined that the tumor positive for mutated BRAF, uncovering a novel c.1799_1803delinsAT; p.V600-K601>D variant. We uncovered this atypical BRAF mutation with 2 different sequencing methods, both in the primary lesion and in 1 metastasis. The patient was immediately treated with vemurafenib as monotherapy and achieved a prolonged (5.5-month) positive response.
  
  
  CONCLUSIONS
  We analyzed the consequences of the BRAF V600-K601>D mutation in terms of amino acids. We referred to the published data and databases to screen chemical properties of well-known BRAF V600 mutations and other complex BRAF mutations to find common features of activated BRAF mutations. Importantly, we highlighted that both the site of the mutation and the involved amino acids are important to predict vemurafenib response. Our conclusion is that complex BRAF mutation surrounding codon 600 could also be sensitive to BRAF inhibitors.
authors.affiliation: Institut Albert Bonniot INSERM/UJF U823, Grenoble, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Busser
authors.affiliation: Institut Albert Bonniot INSERM/UJF U823, Grenoble, France.
authors.forename: Marie Therese
authors.initials: MT
authors.lastname: Leccia
authors.affiliation: Department of Neurosurgery, CHRU Grenoble University Hospital, Grenoble, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Gras-Combe
authors.affiliation: Department of Medical Imaging, CHRU Grenoble University Hospital, Grenoble, France.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bricault
authors.affiliation: Department of Dermatology, CHRU Grenoble University Hospital, Grenoble, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Templier
authors.affiliation: Department of Dermatology, CHRU Grenoble University Hospital, Grenoble, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Claeys
authors.affiliation: Department of Cancer Clinical Chemistry, CHRU Grenoble University Hospital, Grenoble, France.
authors.forename: Marie Jeanne
authors.initials: MJ
authors.lastname: Richard
authors.affiliation: Department of Cancer Clinical Chemistry, CHRU Grenoble University Hospital, Grenoble, France.
authors.forename: Florence
authors.initials: F
authors.lastname: de Fraipont
authors.affiliation: Institut Albert Bonniot INSERM/UJF U823, Grenoble, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Charles
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D017422:Sequence Analysis, DNA; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics; D013449:Sulfonamides / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf